Alzheimer's Disease is a progressive, neurodegenerative disorder characterized by memory impairment and cognitive dysfunction. AD is characterized pathologically by the accumulation of senile (neuritic) plaques, neurofibrillary tangles, amyloid deposition in neural tissues and vessels, synaptic loss, and neuronal death. It is the most common form of dementia and it now represents the third leading cause of death after cardiovascular disorders and cancer. The cost of Alzheimer's Disease is enormous (greater than $100 billion annually in the U.S.) and includes the suffering of the patients, the suffering of families, and the lost productivity of patients and caregivers. As the longevity of society increases, the occurrence of AD will markedly increase. It is estimated that more than 10 million Americans will suffer from AD by the year 2020, if methods for prevention and treatment are not found. Currently, AD is estimated to afflict 10% of the population over age 65 and up to 50% of those over the age of 85. There is currently no effective treatment.
There have been many theories relating to the etiology and pathogenesis of AD. These theories were either based on analogies with other diseases and conditions (e.g., slow virus and aluminum theories), or based on pathologic observations (e.g., cholinergic, amyloid, or tangle theories). Genetic analysis can potentially differentiate between competing theories. The identification of mutations in the β-amyloid precursor protein (β-APP) of individuals prone to early onset forms of AD and related disorders strongly supports the amyloidogenic theories.
The β-amyloid precursor protein (β-APP), a large membrane spanning glycoprotein found in tissues of mammals, including humans, is encoded by a gene on the long arm of human chromosome 21. The main constituent of the plaques, tangles and amyloid deposits is known to be β-amyloid peptides (β-AP), composed of approximately 39 to 43 amino acid fragments of β-APP, and in particular, the 40 amino acid fragment known as Aβ1-40. Several lines of evidence support the involvement of β-AP in the pathogenesis of AD lesions. β-AP and related fragments have been shown to be toxic for PC-12 cell lines and primary cultures of neurons, as well as causing neuronal degeneration with accompanying amnesia in rodents. Strong evidence for the role of β-AP in AD consists of observations of genetic β-APP mutations in individuals with certain forms of Familial Alzheimer's Disease (FAD) and the correlation of disease onset with altered release of β-AP fragments.
It is presently believed that the development of amyloid plaques in the brains of AD patients is a result of excess production and/or reduced clearance or removal of β-AP. It is known that a basal level of β-AP production may be a normal process and that multiple pathways for cleavage of β-APP exist. Currently, however, it is unclear which classes of proteinases or inhibitors thereof that would be effective in treating AD. Various peptidergic compounds and their pharmaceutical compositions have been disclosed as useful in inhibiting or preventing amyloid protein deposits in brains of AD and Down's Syndrome patients.
N-cycloalkyl benzenesulfonamides have been disclosed. See, for example, the following patents and publications: Hermann, R. German patent 195 48 825 A1, 1995; Mittendorf, J. et al. U.S. Pat. No. 5,962,724, 1999; Mittendorf, J. et al. U.S. Pat. No. 5,770,622, 1998; Mittendorf, J. et al. U.S. Pat. No. 5,631,291, 1997; Mittendorf, J. et al. U.S. Pat. No. 5,739,160, 1998; Mittendorf, J. et al. U.S. Pat. No. 5,321,042, 1994; Kunisch, F. et al. U.S. Pat. No. 5,276,169, 1994; Mittendorf, J. et al. PCT patent application WO 95/19337, 1995; Watanabe, F. and Hiroshige, T. PCT patent application, WO 00/46189, 2000; Armarego, W. L. F. and Reece, P. A. J. Chem. Soc. Perkin Trans. 1 1974, 2313; and Levin, J. I. et al. Bioorganic Med. Chem. Lett. 2001, 11, 239. Nothing in these references teaches or suggests the novel compounds of this invention or their use as inhibitors of β-AP production.